View clinical trials related to Cerebellar Ataxias.
Filter by:Cerebellar ataxias are a group of rare neurological disorders that are clinically and genetically heterogeneous, with several hundred genes and diseases known to date. Over the last decade, their diagnosis has been revolutionised by the development of high-throughput sequencing technologies such as exome/genome sequencing (ES/GS), making it possible to obtain a molecular diagnosis in a growing number of patients. However, almost 40% of patients remain without a molecular diagnosis, raising questions about the limitations of sequencing technologies based on a technique known as short-read. One limitation of short-read is its poor ability to detect repeated motif expansions, a frequent mechanism in neurology and associated with more than thirty neurogenetic diseases. Although tools for analysing ES/GS data have gradually been developed in response to this problem, their effectiveness and reliability remain moderate. To date, the gold standard for detecting these expansions remains targeted approaches such as PCR and Southern blot, which are long, tedious and costly processes that require an independent search for each expansion, forcing clinicians to select expansions and limiting diagnostic yield. In addition, there are diseases associated with expansions so rare that no French laboratory offers a diagnostic test. The recent development of long fragment genome sequencing (long-read - lrGS) could provide a solution to all these problems. These technologies are based on a sequencing process during which DNA is preserved in the form of large molecules of several tens of thousands of bases. Regions of the genome containing expansions can therefore be studied directly in their entirety, avoiding the difficulties of reconstruction from small fragments, which is the case in short-read sequencing. In addition, lrGS can characterize the size of repeated motifs and thus detect any causal expansion in an individual in a single analysis. A number of recently published studies, particularly in neurology, have demonstrated the ability of lrGS to detect pathologies with known expansions (SCA36, C9ORF72), but also to discover new ones and thus explain the molecular basis of rare pathologies (SCA27b, NOTCH2NLC). Although these sequencing technologies have been around for a number of years, access is still restricted to research work and is limited by their higher cost. Their value as a second-line diagnostic tool has yet to be demonstrated. The investigators propose to evaluate the feasibility and diagnostic yield of Oxford Nanopore lrGS in duo or trio (patients + 1 or 2 first-degree relatives) in patients with cerebellar ataxia without molecular diagnosis after short-read GS. This will be the first study to transfer this lrGS technique to the second line, in real-life conditions, for the causal genetic diagnosis of cerebellar ataxia.
Cerebellar ataxias (CA) and spastic paraplegias (SP) are genetically and clinically very heterogeneous. More than 40 loci are already known but the number of phenotypes is even greater suggesting further genetic heterogeneity. These progressive disorders are often severe and fatal, due to the absence of specific therapy. The SPATAX network combines the experience of European clinicians and scientists working on these groups of diseases. Over the past year, they have assembled the largest collection of families and achieved a number of tasks (initiation of a clinical and genetic database, distribution of DNA to participating laboratories, mapping of three new loci, and refinement of several loci). In addition to clinicians from Europe and Mediterranean countries, who play a major role in collecting families according to evaluation tools developed and validated by the SPATAX members, the group includes major European laboratories devoted to the elucidation of the molecular basis of these disorders. Each laboratory will centralize all families with a subtype of autosomal recessive (AR) CA (n=116) or SP (n=207) in order to efficiently map and identify the responsible gene(s). Genome-wide scans are already underway in 61 families. Given the expertise of the participants, the researchers expect to map and identify several genes during the course of this project. The spectrum of mutations and phenotype/genotype correlations will be analysed thanks to this unique series of patients with various phenotypes. The knowledge gained will be immediately applicable to patients in terms of improved positive diagnosis, follow-up and appropriate genetic counselling. In the long term, models for genetic entity will be developed in order to understand the pathophysiology and to identify new targets for treatment. The series of patients assembled and the precise knowledge of natural history will facilitate the implantation of therapeutic trials based on rational approaches.